1. Field of the Invention
The present invention relates to a process for preparing hydrochloride-free 2-dihaloacyl-3-aminoacrylic esters by reacting acid fluorides with dialkylaminoacrylic acid derivatives.
2. Description of Related Art
2-Dihaloacyl-3-aminoacrylic esters of the formula (I) are valuable intermediates for the preparation of dihalomethyl-substituted pyrazolylcarboxylic acid derivatives, which can serve as precursors of active fungicidal ingredients (cf. WO 03/070705).
Tetrahedron Lett. 1996, 37, 8751-8754 already discloses that trihaloacylated aminoacrylic esters are obtained when the corresponding chloroacroleins are reacted with a substituted amine. The chloroacroleins required as starting materials are obtained from the corresponding trihaloacetoacetates by means of a Vilsmeier reaction. One disadvantage of this process is that phosphorus oxide trichloride has to be used in the Vilsmeier reaction, and another is that the overall yields are not satisfactory on the industrial scale.
EP-A-1 000 926 teaches that trihaloacylaminopropenoates are obtained by reacting trihaloacetoacetates with dialkylformamide acetals. A disadvantage here is that the deacylated compound occurs as a by-product and has to be removed from the desired product, which leads to additional costs and yield losses.
WO 03/051820 teaches that 2-perhaloacyl-3-aminoacrylic acid derivatives can be obtained by reacting 3-aminoacrylic esters with perhaloalkylcarboxylic anhydrides. However, the process described is not suitable for preparing dihaloacyl-substituted aminoacrylic acid derivatives, since hydrogen chloride is eliminated in the presence of an α-hydrogen, in the presence of tri-ethylamine The dihaloketenes thus formed are very unstable compounds (cf. J. Org. Chem. 1968, 33, 816), which tend to polymerize.
WO 2005/042468 discloses that 2-perhaloacyl-3-aminoacrylic acid derivatives can be obtained by reacting 3-aminoacrylic esters with acid halides in the presence of an organic base. These processes form equimolar amounts of salts, for example hydrochlorides, which have to be removed from the product by filtration or aqueous workup. If the term “hydrochlorides” is used hereinafter, in connection with the invention, the term shall encompass all impurities which form through the reaction with the base, for example hydrochlorides, HCl, other salts. Merely by filtration, however, the products cannot be removed fully from the hydrochlorides, and so certain amounts of the hydrochlorides remain in the product. In many cases, an aqueous workup is also unsuitable, since numerous 2-perhaloacyl-3-aminoacrylic acids, for example 2,2-difluoroacetyl-3-aminoacrylic acid, are hydrolysis-sensitive.
Moreover, the use of an organic base makes the process more expensive and leads to additional wastes.
The full removal of the hydrochlorides from the 2-perhaloacyl-3-aminoacrylic esters is, however, of great synthetic significance, since their reaction with alkylhydrazines impairs the regioselectivity of the ring closure as a result of the presence of HCl or hydrochlorides. For instance, it has been observed that, in the presence even of only small amounts of hydrochlorides, the proportion of the undesired regioisomeric 5-haloalkyl-4-carboxylic acid-pyrazole grows disproportionately.
For example, U.S. Pat. No. 5,498,624 teaches that 3-difluoromethylpyrazole derivatives can be obtained when 2-(difluoroacetyl)-3-alkoxyacrylates are reacted with hydrazines in protic solvents. Here too, the yields of the process leave something to be desired, since a high percentage of the undesired isomeric pyrazoles forms and the isolation of the desired isomers gives rise to further losses. The industrial employment of such a process is therefore scarcely possible for economic reasons.
The ring closure reaction of alkoxyacrylates with hydrazine derivatives forms a high percentage (up to 88%) of the undesired 5-haloalkyl-4-carboxylic acid-pyrazole (cf. J. Het. Chem. 1987, 24, 693).
The dihalomethylalkoxyacrylates are prepared from dihaloacetoacetic esters. Dihaloacetoacetic esters are commercially unavailable and their preparation is technically demanding, since it entails, for example, the use of ketene. The compounds are therefore not preparable in an economically viable manner.
WO 03/051820 discloses that 2-perhaloacyl-3-aminoacrylic acid derivatives can be reacted with hydrazines to give 3-perhalo-substituted pyrazoles. Although use of an aprotic solvent allows the formation of the undesired isomer to be lowered, it is still considerable on application to the inventive dihalogen compounds.